WO04003019 and WO2008/096158 disclose anti-serum albumin (SA) binding moieties, such as anti-SA immunoglobulin single variable domains (dAbs), which have therapeutically-useful half-lives. These documents disclose monomer anti-SA dAbs as well as multi-specific ligands comprising such dAbs, e.g., ligands comprising an anti-SA dAb and a dAb that specifically binds a target antigen, such as TNFR1. Binding moieties are disclosed that specifically bind serum albumins from more than one species, e.g. human/mouse cross-reactive anti-SA dAbs.
WO05118642 and WO2006/059106 disclose the concept of conjugating or associating an anti-SA binding moiety, such as an anti-SA immunoglobulin single variable domain, to a drug, in order to increase the half-life of the drug. Protein, peptide and new chemical entity (NCE) drugs are disclosed and exemplified. WO2006/059106 discloses the use of this concept to increase the half-life of insulintropic agents, e.g., incretin hormones such as glucagon-like peptide (GLP)-1. Reference is also made to Holt et al, “Anti-Serum albumin domain antibodies for extending the half-lives of short lived drugs”, Protein Engineering, Design & Selection, vol 21, no 5, pp 283-288, 2008. WO2008/096158 discloses DOM7h-11, which is a good anti-SA dAb. It would be desirable to provide improved dAbs that are variants of DOM7h-11 and that specifically bind serum albumin, preferably albumins from human and non-human species, which would provide utility in animal models of disease as well as for human therapy and/or diagnosis. It would also be desirable to provide for the choice between relatively modest- and high-affinity anti-SA binding moieties (dAbs). Such moieties could be linked to drugs, the anti-SA binding moiety being chosen according to the contemplated end-application. This would allow the drug to be better tailored to treating and/or preventing chronic or acute indications, depending upon the choice of anti-SA binding moiety. It would also be desirable to provide anti-SA dAbs, that are monomeric or substantially so in solution. This would especially be advantageous when the anti-SA dAb is linked to a binding moiety, e.g., a dAb, that specifically binds a cell-surface receptor, such as TNFR1, with the aim of antagonizing the receptor. The monomeric state of the anti-SA dAb is useful in reducing the chance of receptor cross-linking, since multimers are less likely to form which could bind and cross-link receptors (e.g., TNFR1) on the cell surface, thus increasing the likelihood of receptor agonism and detrimental receptor signaling.
A number of improved dAbs are disclosed in PCT/EP2010/052008 and PCT/EP2010/052007 the disclosures of which are incorporated by reference.
It would also be desirable to provide improved dAbs that have an improved stability. This would be advantageous in allowing a dAb to have a suitable stability profile or shelf-life. In particular, it would be desirable to provide dAbs having an improved ability to resist unfolding upon exposure to elevated temperatures i.e. improved thermostability. It would also be desirable to provide dAbs that have improved stability when formatted into constructs such as multi-specific ligands or when conjugated to proteins, peptides or NCEs.